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CN104039779B - Crystal formation of Azilsartan potassium and preparation method thereof and application thereof - Google Patents

Crystal formation of Azilsartan potassium and preparation method thereof and application thereof Download PDF

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CN104039779B
CN104039779B CN201380005090.7A CN201380005090A CN104039779B CN 104039779 B CN104039779 B CN 104039779B CN 201380005090 A CN201380005090 A CN 201380005090A CN 104039779 B CN104039779 B CN 104039779B
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crystal formation
potassium
azilsartan
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potassium salt
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CN104039779A (en
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雷鑫
吕志卿
王天明
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RUYUAN HEC PHARM Co.,Ltd.
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Ru Yuan Dongyang Light Pharmaceutcal Corp Ltd
Guangdong HEC Pharmaceutical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

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Abstract

The present invention relates to medicinal chemistry art, disclose the crystal formation of Azilsartan potassium salt, the crystal formation of described Azilsartan potassium salt is essentially pure.Described crystal formation is crystal formation A, crystal formation B, crystal formation C, crystal formation D, crystal formation G, crystal formation H, crystal formation I, crystal formation J, crystal formation K or crystal formation L.The crystal formation of essentially pure Azilsartan potassium salt of the present invention has good performance, and bioavailability is high；Having good performance in terms of static behaviour, static behaviour is low, beneficially operates in production technology；And excellent performance in terms of reducing clinic contraction pressure (SBP) and 24 hourly average clinics contraction pressure, therefore can be used for preparation prevention or treats the medicine of hypertension.Use preparation method of the present invention, the Azilsartan potassium salt crystal formation that Azilsartan potassium salt is essentially pure can be prepared, and synthesis technique meets factory's GMP production requirement, be suitable for industrialized production.

Description

Crystal formation of Azilsartan potassium and preparation method thereof and application thereof
Technical field
The present invention relates to medicinal chemistry art, be specifically related to the novel crystal forms of Azilsartan potassium salt, comprise Azilsartan The pharmaceutical composition of potassium crystal formation, and its production and use.
Background technology
Azilsartan, also referred to as (5-methyl-2-oxo-1,3-dioxole-4-base) methyl 2-ethyoxyl- 1-{ [2 '-(5-oxo-4,5-dihydro-1,2,4-diazole-3-bases) biphenyl-4-base] methyl }-1H-benzimidazole-7-carboxylic acid Ester, shown in formula I, Azilsartan is the prodrug of Angiotensin Ⅱ receptor antagonist Azilsartan (TAK-536) to structure, uses In treatment adult hypertension, every day is oral once, and Azilsartan can be used alone and can also join with other resisting hypertension Close and use
Its structure of the potassium salt of Azilsartan is as shown in Formula II:
Wu Tian company discloses Azilsartan potassium salt in patent US7157584 first, and description describes it and prepares Method, by (5-methyl-2-oxo-1,3-dioxole-4-base) methyl-2-ethyoxyl-1-{ [2 '-(5-oxo-4, 5-dihydro-1,2,4-oxadiazoles-3-bases) biphenyl-4-base] methyl }-1H-benzimidazole-7-carboxylate is dissolved in acetone, adds 2 ethyl hexanoic acid potassium solution, the mixture of gained stands overnight in refrigerator, filters the crystal separated out, and room temperature under reduced pressure is dried To the potassium salt of Azilsartan, its fusing point is 196 DEG C.
But, obtained Azilsartan potassium crystal formation is not sufficiently characterized by US7157584, therefore, and Wo Menwu Method knows the crystal form state of the Azilsartan potassium salt obtained by this obtained patent.
A kind of medicine such as Azilsartan potassium there may be different crystalline forms, and the different crystal forms of same medicine is outside The aspects such as sight, dissolubility, fusing point, dissolution, biological effectiveness there may be dramatically different, also can be to the stability of medicine, life Thing availability and curative effect produce different impacts.Accordingly, it would be desirable to have more preferable physicochemical properties, the most relatively high dissolving Degree, bioavailability and the Azilsartan potassium novel crystal forms of curative effect.Be also required to study a kind of low cost, industry friendly preparation Ah The technique of Qi Shatan ester potassium novel crystal forms.
Summary of the invention
Term " crystal formation " refers to a unique ordered arrangement and/or the conformation of the molecule in compound lattice.
Term " essentially pure " refers to that a kind of crystal formation is essentially free of one or more other crystal formations, and its crystal formation is pure Degree at least 60%, or at least 70%, or at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, Or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or At least 99.9%, or its crystal formation contains other crystal formation, and other crystal formations described are less than at cumulative volume or the percentage by weight of crystal formation 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01。
Term " is essentially free of " one or more other crystal formations and refers to that the content of other crystal formation is in cumulative volume or weight Middle percentage ratio is less than 20%, or less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.
Term X-ray powder diagram " substantially as shown in Figure shown " refers in X-ray powder diagram at least 50%, or The peak of at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% occurs in its figure In.
Term " relative intensity " refers to that in all diffraction maximums of X-ray powder diagram, the intensity at the last the first peak is 100% Time, the ratio of the intensity at the intensity at other peak and the last the first peak.
Term " anti-solvent " refers to promote the solvent that solution reaches supersaturation state or crystallization.In some embodiments In, Azilsartan potassium dissolubility in anti-solvent is less than 0.001g/L, or less than 0.01g/L or less than 0.1g/L or little In 0.2g/L, or less than 0.3g/L, or less than 0.4g/L, or less than 0.5g/L, or less than 0.6g/L, or less than 0.8g/L, or Less than 1g/L, or less than 2g/L, or less than 3g/L, or less than 4g/L, or less than 5g/L, or less than 6g/L, or less than 7g/L, or Less than 8g/L, or less than 9g/L, or less than 10g/L.
Term " room temperature " refer to temperature at about 18 DEG C to about 30 DEG C, or about 20 DEG C to 24 DEG C, or about 22 DEG C.
Term " room temperature " refers to that temperature is about 18 DEG C to about 30 DEG C, or about 20 DEG C to about 24 DEG C or about 22 ℃。
When referring to that in collection of illustrative plates and/or figure, the term " peak " of data refers to that those skilled in the art will not belong to background noise A feature.
Numeral in the present invention is approximation, the most whether uses the wording such as " about " or " about ".The numerical value of numeral has It is possible that the difference such as 1%, 2%, 5%, 7%, 8%, 10%, 15% or 20%.Whenever disclosing a numeral with N value Time, any have N+/-1%, N+/-2%, N+/-3%, N+/-5%, N+/-7%, N+/-8%, N+/-10%, N+/-15% Or the numeral of N+/-20% value can be specifically disclosed, wherein " +/-" refers to add deduct.Whenever disclosing the one of a numerical range Individual lower limit, RL, and a upper limit, RU, time, any numerical value being within the scope of the disclosed can be specifically disclosed.Especially Be, contain following should in the range of disclosed numerical value: R=R clearlyL+K*(RU-RL), wherein K be one by 1% increment increase Add from 1% to 100% variable, it may be assumed that 1%, 2%, 3%, 4%, 5%, 50%, 51%, 52% 95%, 96%, 97%, 98%, 99% or 100%.It addition, be disclosed that the above-mentioned numerical value model with two R definition the most clearly Enclose
The invention provides novel crystal forms of Azilsartan potassium and preparation method thereof.
This provide the novel crystal forms of Azilsartan potassium.The medicine of different crystal forms has different chemical and physical property bag Include fusing point, chemism, apparent solubility, dissolution, optically and mechanically performance, vapour pressure and density.The direct shadow of these characteristics Ring process and the production of medicine, and the stability of medicine, dissolubility and bioavailability can be affected.Therefore, Azilsartan potassium Polymorphs body impact comprise the quality of medicine, safety and the effectiveness of Azilsartan potassium crystal formation.
Whether high spot reviews of the present invention Azilsartan potassium exist polymorphic, unexpectedly, it has been found that Azilsartan The multiple novel crystal forms of ester potassium, described novel crystal forms includes crystal formation A, crystal formation B, crystal formation C, crystal formation D, crystal formation E, crystal formation F, crystal formation G, crystal formation H, crystal formation I, crystal formation J, crystal formation K and crystal formation L.In certain embodiments, the novel crystal forms of described Azilsartan potassium is the purest Clean.
The novel crystal forms of Azilsartan potassium of the present invention has good dissolubility and heat stability, in specific system Agent has more preferable bioavailability and stripping curve；Its good permeability and heat stability are suitable in specific pharmaceutical preparation Middle use.Ask；The novel crystal forms of Azilsartan potassium has good performance in terms of static behaviour, and static behaviour is low, is conducive to producing Technique operates；And excellent performance in terms of reducing clinic contraction pressure (SBP) and 24 hourly average clinics contraction pressure, therefore may be used For preparing prevention or the medicine for the treatment of hypertension.
In certain embodiments, the crystal formation of described Azilsartan potassium is crystal formation A.In certain embodiments, described A Qi Husky smooth ester potassium crystal formation A is essentially pure.In certain embodiments, about at 2 θ in the X-ray powder diagram of crystal formation A It is that 7.41 positions have peak.In certain embodiments, the X-ray powder diagram of crystal formation A it is about 7.41,22.83 at 2 θ At put or there is peak many places.In certain embodiments, the X-ray powder diagram of crystal formation A is about 7.41 at 2 θ, At the one of 10.74,18.19,22.83,23.29,23.66 and 24.8 positions or there is peak many places.In certain embodiments, its X-penetrates Line powder diagram is about 4.50,7.41,8.97,9.29,10.74,10.91,12.54,13.74,14.55 at 2 θ, 14.87,15.52,15.98,16.49,17.80,18.19,18.66,18.90,19.38,19.74,20.03,20.57, 21.55,21.91,22.83,23.29,23.67,24.20,24.50,24.80,25.11,25.63,26.68,27.30, 28.32,28.77,29.34,29.95,31.71 at the one of with 32.54 positions or there is peak many places.In certain embodiments, described The X-ray powder diagram of crystal formation A substantially as shown in, wherein the angle of diffraction 2 θ be 7.41 the relative intensity at peak be more than 50%, or more than 60%, or more than 70%, or more than 80%, or more than 90%, or more than 99%.
In certain embodiments, crystal formation A can also detect by the most known analytical technology, identify, classify and characterize, Such as, but not limited to infrared (IR) spectrum, differential scanning calorimetry (DSC), using DSC detection, the fusing point of crystal formation A is of about 200.2 DEG C to about 213.7 DEG C.
In certain embodiments, the crystal formation of described Azilsartan potassium is crystal formation B.In certain embodiments, described A Qi Husky smooth ester potassium crystal formation B is essentially pure.In certain embodiments, about at 2 θ in the X-ray powder diagram of crystal formation B It is that 23.11 positions have peak.In certain embodiments, the X-ray powder diagram of crystal formation B is about 23.01 at 2 θ, 23.11,26.01,28.32 at the one of position or there is peak many places.In certain embodiments, the X-ray powder diagram of crystal formation B In be about 5.79,5.99,15.56,18.36,20.07,20.30,20.93,23.01,23.11,23.3 7,25.24 at 2 θ, 25.65,26.01,27.12,28.32 at the one of position or there is peak many places.In one embodiment, its X-ray powder diagram In be about 5.79,5.99,11.54,13.30,14.68,15.56,16.31,18.36,20.07,20.3 0,20.66 at 2 θ, 20.93,21.08,22.01,22.40,23.01,23.11,23.37,25.24,25.65,26.01,26.64,27.12, 28.32,29.53,29.99,32.98,33.10,36.48 at the one of position or there is peak many places.In certain embodiments, described crystalline substance The X-ray powder diagram of type B substantially as shown in Figure shown in 2, wherein the angle of diffraction 2 θ be 23.11 the relative intensity at peak be more than 50%, or more than 60%, or more than 70%, or more than 80%, or more than 90%, or more than 99%.
In certain embodiments, crystal formation B can also detect by the most known analytical technology, identify, classify and characterize, Such as, but not limited to infrared (IR) spectrum, differential scanning calorimetry (DSC), using DSC detection, the fusing point of crystal formation B is of about 211.4 DEG C to about 218.8 DEG C.
In certain embodiments, the crystal formation of described Azilsartan potassium is crystal formation C.In certain embodiments, described A Qi Husky smooth ester potassium crystal formation C is essentially pure.In certain embodiments, about at 2 θ in the X-ray powder diagram of crystal formation C It is that 6.20 positions have peak.In one embodiment, the X-ray powder diagram of crystal formation C it is about 6.20,18.70 at 2 θ At put or there is peak many places.In certain embodiments, the X-ray powder diagram of crystal formation C is about 6.20 at 2 θ, 12.64,13.36,14.48,16.00,18.70,20.30,21.38,22.78,23.80,25 at the one of .04 position or many places have Peak.In one embodiment, its X-ray powder diagram is about 6.20,12.64,13.36,14.02,14.48 at 2 θ, 16.00,17.74,18.12,18.70,20.30,21.38,22.78,23.80,25.04,25.60,27.52,28.16, 28.32,31.32 at the one of position or there is peak many places.In certain embodiments, the X-ray powder diagram base of described crystal formation C In basis as it is shown on figure 3, wherein the angle of diffraction 2 θ be the relative intensity at peak of 6.20 more than 50%, or more than 60%, or be more than 70%, or more than 80%, or more than 90%, or more than 99%.
In certain embodiments, crystal formation C can also detect by the most known analytical technology, identify, classify and characterize, Such as, but not limited to infrared (IR) spectrum, differential scanning calorimetry (DSC), using DSC detection, the fusing point of crystal formation C is of about 212.8 DEG C to about 223.8 DEG C；In certain embodiments, using DSC detection, the fusing point of crystal formation C is of about 221.4 DEG C to greatly About 223.8 DEG C；In one embodiment, using DSC detection, the fusing point of crystal formation C is of about 218.3 DEG C to about 223.0 DEG C；? In one embodiment, using DSC detection, the fusing point of crystal formation C is of about 214.7 DEG C to about 221.3 DEG C；In some embodiments In, using DSC detection, the fusing point of crystal formation C is of about 217.2 DEG C to about 222.3 DEG C；In certain embodiments, crystal formation C's is red (IR) spectrum is substantially as shown in Figure shown in 4 outward.
In certain embodiments, the crystal formation of described Azilsartan potassium is crystal formation D.In certain embodiments, described A Qi Husky smooth ester potassium crystal formation D is essentially pure.In certain embodiments, about at 2 θ in the X-ray powder diagram of crystal formation D It is that 6.18 positions have peak.In certain embodiments, the X-ray powder diagram of crystal formation D it is about 6.18,18.62 at 2 θ At put or there is peak many places.In certain embodiments, the X-ray powder diagram of crystal formation D is about 6.18 at 2 θ, 15.22,18.62,19.34,23.54,24.88,26.94 at the one of position or there is peak many places.In one embodiment, its X-penetrates Line powder diagram is about 6.18,12.14,12.90,14.26,14.84,15.22,18.62,19.34,20.16 at 2 θ, 21.62,23.54,24.88,26.94 at the one of position or there is peak many places.In certain embodiments, the X-ray powder of crystal formation D Diffraction pattern is about 6.18,12.14,12.90,13.64,14.26,14.84,15.22,17.38,18.04,18. 62 at 2 θ, 19.34,20.16,21.62,22.30,22.76,23.54,24.40,24.88,26.08,26.94,27.74,31.56,34.06 At the one of position or there is peak many places.In certain embodiments, the X-ray powder diagram of described crystal formation D is substantially as shown in Figure 5 institutes Show, wherein the angle of diffraction 2 θ be the relative intensity at peak of 6.18 more than 50%, or more than 60%, or more than 70%, or greatly In 80%, or more than 90%, or more than 99%.
In certain embodiments, crystal formation D can also detect by the most known analytical technology, identify, classify and characterize, Such as, but not limited to infrared (IR) spectrum, differential scanning calorimetry (DSC), using DSC detection, the fusing point of crystal formation D is of about 205.6 DEG C to about 220.1 DEG C；In certain embodiments, using DSC detection, the fusing point of crystal formation D is of about 206.6 DEG C to greatly About 216.2 DEG C；In one embodiment, using DSC detection, the fusing point of crystal formation D is of about 205.6 DEG C to about 216.7 DEG C；? In one embodiment, using DSC detection, the fusing point of crystal formation D is of about 214.8 DEG C to about 220.1 DEG C；In some embodiments In, using DSC detection, the fusing point of crystal formation D is of about 206.4 DEG C to about 214.3 DEG C；In certain embodiments, crystal formation D's is red (IR) spectrum is substantially as shown in Figure shown in 6 outward.
In certain embodiments, the crystal formation of described Azilsartan potassium is crystal formation E.In certain embodiments, described A Qi Husky smooth ester potassium crystal formation E is essentially pure.In certain embodiments, about at 2 θ in the X-ray powder diagram of crystal formation E It is that 6.16 positions have peak.In certain embodiments, the X-ray powder diagram of crystal formation E it is about 6.16,28.28 at 2 θ At put or there is peak many places.In certain embodiments, the X-ray powder diagram of crystal formation E is about 6.16 at 2 θ, 13.34,16.22,18.58,19.88,21.46,22.86,26.84,28.28,33.62 at the one of position or there is peak many places.? In some embodiments, the X-ray powder diagram of described crystal formation E is substantially as shown in Figure, shown in 7, wherein the angle of diffraction 2 θ is 6.16 The relative intensity at peak is more than 50%, or more than 60%, or more than 70%, or more than 80%, or more than 90%, or More than 99%.
In certain embodiments, crystal formation E can also detect by the most known analytical technology, identify, classify and characterize, Such as, but not limited to infrared (IR) spectrum, differential scanning calorimetry (DSC), using DSC detection, the fusing point of crystal formation E is of about 198.3 DEG C to about 208.4 DEG C；In certain embodiments, infrared (IR) spectrum of crystal formation E is substantially as shown in Figure shown in 8.
In certain embodiments, the crystal formation of described Azilsartan potassium is crystal formation F.In certain embodiments, described A Qi Husky smooth ester potassium crystal formation F is essentially pure.In certain embodiments, about at 2 θ in the X-ray powder diagram of crystal formation F Peak is had for 17.96,22.52,23.32 position.In certain embodiments, about at 2 θ in the X-ray powder diagram of crystal formation F Peak is had at the one of 5.90,8.46,17.26,17.96,19.60,21.66,22.52,23.32 position or many places.Real at some Executing in example, the X-ray powder diagram of described crystal formation F is substantially as shown in Figure shown in 9.
In certain embodiments, crystal formation F can also detect by the most known analytical technology, identify, classify and characterize, Such as, but not limited to infrared (IR) spectrum, differential scanning calorimetry (DSC), using DSC detection, the fusing point of crystal formation F is of about 94.2 DEG C to about 111.0 DEG C；In certain embodiments, infrared (IR) spectrum of crystal formation F is substantially as shown in Figure shown in 10.
In certain embodiments, the crystal formation of described Azilsartan potassium is crystal formation G.In certain embodiments, described A Qi Husky smooth ester potassium crystal formation G is essentially pure.In certain embodiments, about at 2 θ in the X-ray powder diagram of crystal formation G It is that 28.28 positions have peak.In certain embodiments, the X-ray powder diagram of crystal formation G is about 6.18,28.28 at 2 θ, At the one of 40.50 positions or there is peak many places.In certain embodiments, the X-ray powder diagram of crystal formation G at 2 θ is about 6.18,13.32,14.10,14.44,16.02,17.80,18.70,21.30,22.70,22.90,23.70,24.38,24.74, 26.90,28.28,40.50 at the one of position or there is peak many places.In certain embodiments, the X-ray powder of described crystal formation G spreads out Penetrate figure substantially as shown in Figure shown in 11, wherein the angle of diffraction 2 θ be the relative intensity at peak of 28.28 more than 50%, or more than 60%, Or more than 70%, or more than 80%, or more than 90%, or more than 99%.
In certain embodiments, crystal formation G can also detect by the most known analytical technology, identify, classify and characterize, Such as, but not limited to infrared (IR) spectrum, differential scanning calorimetry (DSC).
In certain embodiments, the crystal formation of described Azilsartan potassium is crystal formation H.In certain embodiments, described A Qi Husky smooth ester potassium crystal formation H is essentially pure.In certain embodiments, about at 2 θ in the X-ray powder diagram of crystal formation H It is that 6.18 positions have peak.In certain embodiments, the X-ray powder diagram of crystal formation H it is about 6.18,22.80 at 2 θ At put or there is peak many places.In certain embodiments, the X-ray powder diagram of crystal formation H is about 14.10 at 2 θ, 14.36,15.14,15.92,17.34,18.02,18.72,19.24,20.18,21.68,22.80,23.56,24.96, At the one of 27.02,27.60,30.2 positions or there is peak many places.In certain embodiments, in the X-ray powder diagram of crystal formation H It is about that 6.18 positions have peak at 2 θ.In certain embodiments, the X-ray powder diagram of described crystal formation H is substantially as shown in Figure 12 Shown in, wherein the angle of diffraction 2 θ be the relative intensity at peak of 6.18 more than 50%, or more than 60%, or more than 70%, or More than 80%, or more than 90%, or more than 99%.
In certain embodiments, crystal formation H can also detect by the most known analytical technology, identify, classify and characterize, Such as, but not limited to infrared (IR) spectrum, differential scanning calorimetry (DSC), using DSC detection, the fusing point of crystal formation H is of about 213 DEG C to about 218 DEG C.
In certain embodiments, the crystal formation of described Azilsartan potassium is crystal formation I.In certain embodiments, described A Qi Husky smooth ester potassium crystal formation I is essentially pure.In certain embodiments, about at 2 θ in the X-ray powder diagram of crystal formation I It is that 6.06 positions have peak.In certain embodiments, the X-ray powder diagram of crystal formation I is about 6.06,12.10 at 2 θ, 15.00,19.54,23.04 at the one of position or there is peak many places.In certain embodiments, the X-ray powder diagram of crystal formation I In be about 6.06,12.10,13.86,15.00,18.72,19.54,21.54,23.04,23.88,25. 44,28.36 at 2 θ At the one of position or there is peak many places.In certain embodiments, the X-ray powder diagram of described crystal formation I is substantially as shown in Figure 13 institutes Show, wherein the angle of diffraction 2 θ be the relative intensity at peak of 6.06 more than 50%, or more than 60%, or more than 70%, or greatly In 80%, or more than 90%, or more than 99%.
In certain embodiments, crystal formation I can also detect by the most known analytical technology, identify, classify and characterize, Such as, but not limited to infrared (IR) spectrum, differential scanning calorimetry (DSC).
In certain embodiments, the crystal formation of described Azilsartan potassium is crystal formation J.In certain embodiments, described A Qi Husky smooth ester potassium crystal formation J is essentially pure.In certain embodiments, about at 2 θ in the X-ray powder diagram of crystal formation J It is that 13.18 positions have peak.In certain embodiments, the X-ray powder diagram of crystal formation J is about 13.18,23.24 at 2 θ At the one of position or there is peak many places.In certain embodiments, the X-ray powder diagram of crystal formation J is about 13.18 at 2 θ, 15.90,20.18,21.10,22.22,22.52,23.24,23.98 at the one of position or there is peak many places.In certain embodiments, The X-ray powder diagram of crystal formation J is about 5.94,9.04,9.94,11.46,11.88,13.18,14.26 at 2 θ, 14.58,15.90,17.38,17.80,18.10,19.32,20.18,21.10,22.22,22.52,23.24,23.98, 24.96,26.44,27.60,28.30 at the one of position or there is peak many places.In certain embodiments, the X-ray of described crystal formation J Powder diagram substantially as shown in Figure shown in 14, wherein the angle of diffraction 2 θ be the relative intensity at peak of 13.18 more than 50%, or be more than 60%, or more than 70%, or more than 80%, or more than 90%, or more than 99%.
In certain embodiments, crystal formation J can also detect by the most known analytical technology, identify, classify and characterize, Such as, but not limited to infrared (IR) spectrum, differential scanning calorimetry (DSC).
In certain embodiments, the crystal formation of described Azilsartan potassium is crystal formation K.In certain embodiments, described A Qi Husky smooth ester potassium crystal formation K is essentially pure.In certain embodiments, about at 2 θ in the X-ray powder diagram of crystal formation K It is that 15.84 positions have peak.In certain embodiments, the X-ray powder diagram of crystal formation K is about 6.06,13.22 at 2 θ, 15.84,20.14 at the one of position or there is peak many places.In certain embodiments, in the X-ray powder diagram of crystal formation K about It is 6.06,12.48,13.22,13.92,14.34,14.62,15.84,18.60,20.14,20. 92,22.66,23.66 at 2 θ, 24.00,26.86 at the one of position or there is peak many places.In certain embodiments, in the X-ray powder diagram of crystal formation K about It is 6.06,12.48,13.22,13.92,14.34,14.62,15.84,17.62,18.60,19. 36,20.14,20.92 at 2 θ, 21.24,22.66,23.66,24.00,26.86,27.40,28.06,29.04,31.20,32 at the one of .88 position or many places have Peak.In certain embodiments, the X-ray powder diagram of described crystal formation K is substantially as shown in Figure, shown in 15, wherein the angle of diffraction 2 θ is The relative intensity at the peak of 15.84 is more than 50%, or more than 60%, or more than 70%, or more than 80%, or be more than 90%, or more than 99%.
In certain embodiments, crystal formation K can also detect by the most known analytical technology, identify, classify and characterize, Such as, but not limited to infrared (IR) spectrum, differential scanning calorimetry (DSC).
In certain embodiments, the crystal formation of described Azilsartan potassium is crystal formation L.In certain embodiments, described A Qi Husky smooth ester potassium crystal formation L is essentially pure.In certain embodiments, about at 2 θ in the X-ray powder diagram of crystal formation L It is that 20.92 positions have peak.In certain embodiments, the X-ray powder diagram of crystal formation L is about 10.34 at 2 θ, 18.26,20.92,22.10,24.06 at the one of position or there is peak many places.In certain embodiments, the X-ray powder of crystal formation L Diffraction pattern is about 10.34,10.82,14.52,15.52,17.52,18.26,19.00,20.54,20.92 at 2 θ, 21.38,22.10,22.84,23.48,24.06,24.36,25.56 at the one of position or there is peak many places.In certain embodiments, The X-ray powder diagram of crystal formation L is about 7.48,10.34,10.82,12.04,13.10,14.52,15.52 at 2 θ, 16.88,17.52,18.26,19.00,19.62,20.54,20.92,21.38,22.10,22.84,23.48,24.06, 24.36,25.56,26.36 at the one of position or there is peak many places.In certain embodiments, the X-ray powder of described crystal formation L spreads out Penetrate figure substantially as shown in Figure shown in 16, wherein the angle of diffraction 2 θ be the relative intensity at peak of 20.92 more than 50%, or more than 60%, Or more than 70%, or more than 80%, or more than 90%, or more than 99%.
In certain embodiments, crystal formation L can also detect by the most known analytical technology, identify, classify and characterize, Such as, but not limited to infrared (IR) spectrum, differential scanning calorimetry (DSC), use DSC detection.
According to the present invention, the X-ray powder diagram measured by the present invention, it is by the production of Rigaku motor INSTRUMENT MODEL is that the x-ray powder diffraction instrument of D/max-3A records；Testing conditions: Cu target k α 1, voltage 35KV, electric current 25mA, 2 θ Scope: 3 °-50 °, 10 °/min；In X-ray powder diagram, vertical coordinate represents that the diffraction represented with the counting/second (cps) is strong Degree, abscissa represents the angle of diffraction 2 θ that expenditure represents.
Infrared spectrogram measured by the present invention, is to detect on iS10 at INSTRUMENT MODEL；DSC measured by the present invention Collection of illustrative plates is that TA/Q2000 collects by INSTRUMENT MODEL, and sample detects in nitrogen stream, testing conditions: the Ramp40-240 DEG C of speed that heats up 10 DEG C/min of degree.
It should be noted that the X-ray powder diffraction peak for crystal formation, between a machine and another machine with And between a sample and another sample, 2 θ of X-ray powder diffraction spectrum may be slightly changed, its numerical value may phase About 1 degree (°) of difference, or difference about 0.8 °, or difference about 0.5 °, or difference about 0.3 °, or difference is about 0.1 °, therefore given numerical value can not be considered as absolute.
For the DSC of the above crystal formation, between a machine and another machine and a sample and another Between sample, the endothermic peak of DSC collection of illustrative plates may be slightly changed, and its numerical value may differ by about 3 DEG C, or difference about 2 DEG C, Or differ about 1 DEG C, or difference about 0.8 DEG C, or difference about 0.5 DEG C, or difference about 0.3 DEG C, or phase Difference about 0.1 DEG C, therefore given numerical value can not be considered as absolute.
Present invention also offers the preparation method of described Azilsartan potassium salt crystal formation A-L, described preparation method is permissible Any existence form of Azilsartan potassium is changed into existence form expected from another kind.The A Qi that described preparation method obtains The crystal formation of husky smooth ester potassium is selected from crystal formation A, crystal formation B, crystal formation C, crystal formation D, crystal formation E, crystal formation F, crystal formation G, crystal formation H, crystal formation I, crystal formation Presented in one of J, crystal formation K, crystal formation L, the crystal formation of described Azilsartan potassium is essentially pure.
The first method preparing Azilsartan potassium crystal formation is provided here, comprising:
A) Azilsartan is added in solvent form mixture；
B) heating blends or form solution toward adding solvent in mixture；
C) in the solution formed, potassium salt soln is added；
D) crystal is separated out at a suitable temperature.
Azilsartan of the present invention can be prepared by method disclosed in patent US7157584.
Heating blends to obtain solution or part solution completely, heats described mixture to about to certain temperature 40 DEG C of reflux temperatures to solution, or about 55 DEG C to about 65 DEG C.In certain embodiments, about 60 are heated the mixture to ℃.In certain embodiments, backflow is heated the mixture to.
Solvent needed for the Azilsartan of every gram is of about 10ml to about 300ml.In certain embodiments, described potassium Salt reagent is selected from organic acid potassium salt or mineral acid potassium salt or a combination thereof, and some infinite examples of mineral acid potassium salt include nitric acid Potassium, potassium sulfate, potassium sulfite, Potassium bromate., potassium bicarbonate, potassium thiocyanate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, phthalic acid Hydrogen potassium or a combination thereof.The infinite example of some of organic acid potassium salt includes potassium hydrogen phthalate, potassium acetate, potassium formate, phosphoric acid Di tert butyl carbonate potassium, glycyrrhizic acid dipotassium, 2 ethyl hexanoic acid potassium, ehtyl potassium xanthate, potassium sorbate or the combination of mentioned reagent.Phase For Azilsartan, described potassium salt is of about 1.0 equivalents to about 3.0 equivalents, or is of about 1.0 equivalents to about 2.0 Equivalent, or it is of about 1.3 equivalents to about 1.7 equivalents.
Separating out crystal at a suitable temperature, suitable temperature refers to about-20 DEG C to about 20 DEG C, or about 0 DEG C extremely About 10 DEG C, or it is of about 0 DEG C to about 5 DEG C.
The method that the second prepares Azilsartan potassium crystal formation, comprising: at a suitable temperature, Jiang Aqi are provided here Husky smooth ester potassium adds in a kind of solvent or a kind of mixed solvent, forms solution, if it is molten to promote to need to add another kind of solvent The formation of liquid；The solution that cooling is formed is to promote the formation of crystal.
In certain embodiments, suitable temperature refers to about 40 DEG C of reflux temperatures to solvent, the solution that will be formed It is cooled to about-20 DEG C to about 10 DEG C, or about-10 to about 10 DEG C, or about 0 DEG C to about 5 DEG C.In some embodiments In, crystal be formed by the solution that formed of cooling the most again toward addition anti-solvent in the solution after cooling.
In certain embodiments, the first preparation method and the second preparation method of Azilsartan potassium crystal formation is used Solvent include one or more polar solvents, one or more non-polar solvens or a combination thereof.In certain embodiments, described Solvent be dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-Methyl pyrrolidone (NMP), water, ether solvents, ketone Solvent, esters solvent, aromatic hydrocarbon solvent, alkane solvents, nitrile solvents or a combination thereof.In other embodiments, described ether is molten Agent is methyltetrahydrofuran, oxolane, 1,4-dioxane, glycol dimethyl ether or methyl tertiary butyl ether(MTBE) or a combination thereof.? In some embodiments, described ketones solvent is acetone, butanone or butanone or 4-methyl-2 pentanone or a combination thereof.Real at some Execute in example, described esters solvent be ethyl acetate, isopropyl acetate, n-butyl acetate, tert-butyl acetate, sec-butyl acetate or Tert-butyl acetate or a combination thereof.In certain embodiments, described varsol be normal hexane, hexamethylene or pentane or normal heptane, Toluene, dimethylbenzene or a combination thereof；In certain embodiments, described halogenated hydrocarbon solvent be dichloromethane, 1,2-dichloroethanes, chlorine Imitative, carbon tetrachloride or a combination thereof；In certain embodiments, described nitro solvent be nitroethane, nitromethane, Nitrobenzol or its Combination.
Here a kind of method preparing Azilsartan potassium crystal formation A is provided, comprising: Azilsartan is added acetone In, it being heated to backflow and form solution, potassium salt soln is added in the solution formed, dropping acetic acid is 5-6 to pH, suitably At a temperature of formed crystal.
Here a kind of method preparing Azilsartan potassium crystal formation B is provided, comprising: Azilsartan is added acetone In, it is heated to backflow and forms solution, potassium salt soln is added in the solution formed, forms crystal at a suitable temperature.
Preparation method of the present invention, when solvent selected from acetone, 4-methyl-2 pentanone, ethyl acetate, dichloromethane, Dichloroethanes, isobutyl acetate, sec-butyl acetate, methyltetrahydrofuran, nitroethane, 1,2-dichloroethanes, butanone, 1,4-bis- Oxygen six ring, glycol dimethyl ether, acetonitrile, oxolane, hexamethylene or a combination thereof, can obtain essentially pure Azilsartan Ester potassium crystal formation C；It is the mixed solvent of acetone and dioxane in certain embodiments, is glycol dinitrate in certain embodiments Ether and the mixed solvent of acetonitrile, be the mixed solvent of acetone and oxolane in certain embodiments, be in certain embodiments Acetone and the mixed solvent of acetonitrile, be the mixed solvent of acetone and sec-butyl acetate, in some embodiments in certain embodiments In be the mixed solvent of oxolane and dichloroethanes, be the mixed solvent of oxolane and hexamethylene in certain embodiments, It is the mixed solvent of acetone and dichloroethanes in certain embodiments, is that the mixing of acetone and hexamethylene is molten in certain embodiments Agent.
Preparation method of the present invention, when solvent be dioxane, glycol dimethyl ether, acetonitrile, DMSO, acetone or its Combination, can obtain essentially pure Azilsartan potassium crystal formation D；Solvent described in certain embodiments is DMSO and third The mixed solvent of ketone.
Preparation method of the present invention, when solvent is chloroform, can obtain Azilsartan potassium crystal formation E.
Preparation method of the present invention, when solvent is tert-butyl acetate or DMF or a combination thereof, can obtain A Qisha Smooth ester potassium crystal formation F.
Preparation method of the present invention, when solvent is oxolane or carbon tetrachloride or a combination thereof, can obtain Ah Qi Shatan ester potassium crystal formation G.
Preparation method of the present invention, when solvent be glycol dimethyl ether, DMF, toluene, ethyl acetate, dioxane, When sec-butyl acetate or a combination thereof, Azilsartan potassium crystal formation H can be obtained；Solvent described in certain embodiments is second two Diethylene glycol dimethyl ether and the mixed solvent of DMF, the mixed solvent that solvent is toluene and dioxane described in certain embodiments, In some embodiments, described solvent is the mixed solvent of ethyl acetate and dioxane, and in certain embodiments, described is molten Agent is the secondary ethyl ester of acetic acid and the mixed solvent of dioxane.
Preparation method of the present invention, when solvent is acetonitrile or acetone or a combination thereof, can obtain Azilsartan Potassium crystal formation I.
Preparation method of the present invention, when solvent is acetone, water, glycol dimethyl ether, oxolane, DMSO, dichloro When methane, acetonitrile, N-Methyl pyrrolidone or a combination thereof, Azilsartan potassium crystal formation J can be obtained；In certain embodiments, Described solvent is the mixed solvent of acetone and water, and in certain embodiments, described solvent is glycol dimethyl ether and tetrahydrochysene The mixed solvent of furan, or be the mixed solvent of DMSO and dichloromethane, or be the mixed of acetone, glycol dimethyl ether and water Bonding solvent, or be the mixed solvent of acetonitrile and water, or be the mixed solvent of acetonitrile, N-Methyl pyrrolidone and water.
Preparation method of the present invention, when solvent is acetonitrile, obtains Azilsartan potassium crystal formation K.
Preparation method of the present invention, when solvent is oxolane, water, NMP, DMF, dioxane or a combination thereof, Obtain Azilsartan potassium crystal formation L；In certain embodiments, described solvent is the mixed solvent of oxolane and water, or For oxolane and the mixed solvent of NMP, or it it is the mixed solvent of DMF and dioxane.
The novel crystal forms of Azilsartan potassium provided by the present invention has good performance, and such as dissolubility is high；Heat is steady Qualitative；Oral administration biaavailability is high；At specific preparation, there is more preferable bioavailability and stripping curve；Its good infiltration Property and heat stability be suitable in specific pharmaceutical preparation use.The novel crystal forms of Azilsartan potassium provided by the present invention is quiet Electrically aspect has good performance, and static behaviour is low, beneficially operates in production technology.Azilsartan provided by the present invention The novel crystal forms of potassium is excellent performance in terms of reducing clinic contraction pressure (SBP) and 24 hourly average clinics contraction pressure, therefore can be used for Preparation prevention or the medicine for the treatment of hypertension.
The novel crystal forms of Azilsartan potassium provided by the present invention, including crystal formation A, crystal formation B, crystal formation C, crystal formation D, crystal formation E, Crystal formation F, crystal formation G, crystal formation H, crystal formation I, crystal formation J, crystal formation K and crystal formation L are essentially pure.Provided by the present invention preparation Ah The side of Qi Shatan ester potassium novel crystal forms meets factory's GMP production requirement, is suitable for industrialized production.
In certain embodiments, the pharmaceutical composition comprising Azilsartan potassium crystal formation can be further prepared into oral medicine Various solid preparations, including capsule, tablet, pill, powder and granule.These preparations can also include excipient or load Body, described excipient or carrier include sodium citrate, calcium phosphate, filler, binding agent, wetting agent, disintegrating agent, blocker, Absorption enhancer, wetting agent, absorbent or lubricant or their mixture.Wherein, filler includes starch, lactose, sucrose, Glucose, mannitol, silicic acid or a combination thereof；Described binding agent includes carboxymethyl cellulose, alginate, gelatin, polyvinyl pyrrole Ketone, sucrose and arabic gum or a combination thereof；Described wetting agent includes glycerol；Described disintegrating agent includes agar, calcium carbonate, soil Bean starch or tapioca, alginic acid, some silicate and sodium carbonate, low-substituted hydroxypropyl cellulose or a combination thereof；Described Blocker solution such as paraffin；Described absorption enhancer such as quaternary ammonium compounds；Described wetting agent such as hexadecanol and single tristearin Acid glyceride；Described absorbent such as kaolin and Bentonite；Described lubricant such as Pulvis Talci, calcium stearate, magnesium stearate, Gu Body Polyethylene Glycol, sodium laurylsulfate or a combination thereof.
The novel crystal forms of Azilsartan potassium provided by the present invention and the pharmaceutical composition provided may be used for prevention Or treatment hypertension.
Here also provide and be administered and the new crystal form of the Azilsartan potassium disclosed by the invention of effective dose on patient treatment Or the method that pharmaceutical composition prevents or treats hypertension.
Here also providing the use of pharmaceutical composition, it includes treating the crystal formation A of the Azilsartan of effective dose, crystal formation B, crystal formation C, crystal formation D, crystal formation E, crystal formation F, crystal formation G, crystal formation H, crystal formation I, crystal formation J or crystal formation K and one or more pharmaceutically may be used The carrier accepted, excipient or diluent treat the needs of experimenter's situation, such as a powerful and lasting angiotensin II antagonistic activity and hypotensive activity, and insulin-sensitizing activity, and blood circulation diseases such as hypertension and heart disease are (such as the heart Dirty hypertrophy, heart failure, myocardial infarction).
Accompanying drawing explanation
Fig. 1 shows the X-ray powder diagram of Azilsartan potassium salt crystal formation A；
Fig. 2 shows the X-ray powder diagram of Azilsartan potassium salt crystal formation B；
Fig. 3 shows the X-ray powder diagram of Azilsartan potassium salt crystal formation C；
Fig. 4 shows the infrared spectrogram of Azilsartan potassium salt crystal formation C；
Fig. 5 shows the X-ray powder diagram of Azilsartan potassium salt crystal formation D；
Fig. 6 shows the infrared spectrogram of Azilsartan potassium salt crystal formation D；
Fig. 7 shows the X-ray powder diagram of Azilsartan potassium salt crystal formation E；
Fig. 8 shows the infrared spectrogram of Azilsartan potassium salt crystal formation E；
Fig. 9 shows the X-ray powder diagram of Azilsartan potassium salt crystal formation F；
Figure 10 shows the infrared spectrogram of Azilsartan potassium salt crystal formation F；
Figure 11 shows the X-ray powder diagram of Azilsartan potassium salt crystal formation G；
Figure 12 shows the X-ray powder diagram of Azilsartan potassium salt crystal formation H；
Figure 13 shows the X-ray powder diagram of Azilsartan potassium salt crystal formation I；
Figure 14 shows the X-ray powder diagram of Azilsartan potassium salt crystal formation J；
Figure 15 shows the X-ray powder diagram of Azilsartan potassium salt crystal formation K；
Figure 16 shows the X-ray powder diagram of Azilsartan potassium salt crystal formation L.
Detailed description of the invention
Those skilled in the art can use for reference present disclosure, is suitably modified technological parameter and realizes.Special needs to be pointed out is, All similar replacements and change apparent to those skilled in the art, they are considered as being included in this Bright.The product of the present invention is described by preferred embodiment, related personnel substantially can without departing from present invention, In spirit and scope, product as herein described it is modified or suitably changes and combine, realize and apply the technology of the present invention.
In order to be further appreciated by the present invention, below in conjunction with embodiment, the present invention is described in detail.
Embodiment 1: the preparation of Azilsartan potassium salt crystal formation A
Azilsartan (1.0g) is dissolved in the acetone (20mL) of backflow, forms solution, solution is cooled to 50 DEG C, past Solution slowly drips acetone (1mL) solution of 2 ethyl hexanoic acid potassium (0.35g), after being slowly cooled to 0 DEG C, is added dropwise over acetic acid Regulation pH5～6, continues insulated and stirred 5h, filters, is vacuum dried 12h at 45 DEG C and obtains white powder, shows through XRPD testing result White powder is Azilsartan potassium crystal formation A, as shown in Figure 1.
Embodiment 2: the preparation of Azilsartan potassium salt crystal formation B
Azilsartan (1.0g) is dissolved in the acetone (20mL) of backflow, forms solution, after solution is cooled to 50 DEG C It is slowly added into acetone (1mL) solution of 2 ethyl hexanoic acid potassium (0.35g), solution is slowly cooled to 0 DEG C, continue insulated and stirred 5h, filters, and gained solid is Azilsartan potassium crystal formation B through XRPD testing result display sample, as shown in Figure 2.
Embodiment 3 to embodiment 25 is the preparation of Azilsartan potassium salt crystal formation C
Embodiment 3
Azilsartan (1.0g) is dissolved in the acetone (20mL) of backflow, forms solution, after solution is cooled to 50 DEG C Add acetone (1mL) solution of 2 ethyl hexanoic acid potassium (0.35g), solution is slowly cooled to 0 DEG C, continue insulated and stirred 5h, mistake Filter, is vacuum dried 12h and obtains white powder at 45 DEG C, be Azilsartan potassium crystal formation C through XRPD testing result display white powder, As shown in Figure 3.
Embodiment 4
Azilsartan (1.0g) is dissolved in the oxolane (20mL) of backflow, forms solution, solution is cooled to 50 DEG C, add oxolane (2mL) solution of 2 ethyl hexanoic acid potassium (0.5g), after solution is slowly cooled to 0 DEG C, continues insulation and stir Mix 5h, filter, be vacuum dried 12h at 45 DEG C and obtain white powder, be Azilsartan through XRPD testing result display drying sample Potassium crystal formation C.
Embodiment 5
At a reflux temperature, Azilsartan (1.0g) is dissolved in 4-methyl-two pentanone (80mL), forms solution, will Solution is down to add after 50 DEG C 4-methyl-two pentanone (2mL) solution of 2 ethyl hexanoic acid potassium (0.5g), is slowly cooled to 0 DEG C, continues Continuous insulated and stirred 5h, crystal is collected by filtration, is vacuum dried 12h and obtains white powder, show through XRPD testing result at 45 DEG C Drying sample is Azilsartan potassium crystal formation C.
Embodiment 6
At 60 DEG C, Azilsartan (1.0g) is dissolved in ethyl acetate (80mL), forms solution, be down to 50 DEG C, slowly Ethyl acetate (2mL) solution adding 2 ethyl hexanoic acid potassium (0.5g) forms reactant mixture, is slowly lowered the temperature by reactant mixture To 0 DEG C, continue insulated and stirred 5h, crystal is collected by filtration, be vacuum dried 12h at 45 DEG C and obtain white powder, through XRPD testing result Display drying sample is Azilsartan potassium crystal formation C.
Embodiment 7
At 60 DEG C, Azilsartan (1.0g) is dissolved in acetone (80mL), forms solution, after solution is cooled to 50 DEG C It is slowly added to acetone (2mL) solution of 2 ethyl hexanoic acid potassium (0.5g), forms reactant mixture, reactant mixture is slowly lowered the temperature To 0 DEG C, continue insulated and stirred 5h, crystal is collected by filtration, be vacuum dried 12h at 45 DEG C and obtain white powder, through XRPD testing result Display drying sample is Azilsartan potassium crystal formation C.
Embodiment 8
At 60 DEG C, Azilsartan (1.0g) is dissolved in dichloromethane (100mL), forms solution, be down to 50 DEG C, toward molten Liquid is slowly added to acetone (2mL) solution of 2 ethyl hexanoic acid potassium (0.5g), forms reactant mixture, mixture is slowly lowered the temperature To 0 DEG C, continue insulated and stirred 5h, crystal is collected by filtration, be vacuum dried 12h at 45 DEG C and obtain white powder, through XRPD testing result Display drying sample is Azilsartan potassium crystal formation C.
Embodiment 9
At 60 DEG C, Azilsartan (1.0g) is dissolved in isobutyl acetate (90mL), forms solution, be down to 50 DEG C, past Solution is slowly added to isobutyl acetate (2mL) solution of 2 ethyl hexanoic acid potassium (0.5g), forms reactant mixture, by mixture Slowly it is cooled to 0 DEG C, continues insulated and stirred 5h, crystal is collected by filtration, be vacuum dried 12h at 45 DEG C and obtain white powder, through XRPD Testing result display drying sample is Azilsartan potassium crystal formation C.
Embodiment 10
At 60 DEG C, Azilsartan (1.0g) is dissolved in sec-butyl acetate (200mL), forms solution, be down to 50 DEG C, past Solution is slowly added to sec-butyl acetate (2mL) solution of 2 ethyl hexanoic acid potassium (0.5g), forms reactant mixture, by mixture Slowly it is cooled to 0 DEG C, continues insulated and stirred 5h, crystal is collected by filtration, be vacuum dried 12h at 45 DEG C and obtain white powder, through XRPD Testing result display drying sample is Azilsartan potassium crystal formation C.
Embodiment 11
At 60 DEG C, Azilsartan (1.0g) is dissolved in methyltetrahydrofuran (90mL), forms solution, be down to 50 DEG C After, it is slowly added to methyltetrahydrofuran (2mL) solution of 2 ethyl hexanoic acid potassium (0.5g), forms reactant mixture, by mixture Slowly it is cooled to 0 DEG C, continues insulated and stirred 5h, crystal is collected by filtration, be vacuum dried 12h at 45 DEG C and obtain white powder, through XRPD Testing result display drying sample is Azilsartan potassium crystal formation C.
Embodiment 12
At 60 DEG C, Azilsartan (1.0g) is dissolved in nitroethane (130mL), forms solution, after being down to 50 DEG C, slow Slow isobutyl acetate (2mL) solution adding 2 ethyl hexanoic acid potassium (0.5g), forms mixture, mixture is slowly cooled to 0 DEG C, continue insulated and stirred 5h, filter, be vacuum dried 12h at 45 DEG C and obtain white powder, show drying sample through XRPD testing result For Azilsartan potassium crystal formation C.
Embodiment 13
At 60 DEG C, Azilsartan (1.0g) is dissolved in 1, in 2-dichloroethanes (90mL), forms solution, be cooled to 50 DEG C After be slowly added to acetone (2mL) solution of 2 ethyl hexanoic acid potassium (0.5g), be slowly cooled to 0 DEG C, continue insulated and stirred 5h, mistake Filter, is vacuum dried 12h and obtains white powder at 45 DEG C, be Azilsartan potassium crystal formation C through XRPD testing result display drying sample.
Embodiment 14
At 60 DEG C, Azilsartan (1.0g) is joined in butanone (25mL), dissolves, form solution, be cooled to 50 DEG C, Add butanone (2mL) solution of 2 ethyl hexanoic acid potassium (0.5g), reactant mixture is slowly cooled to 0 DEG C, continue insulated and stirred 5h, filters, and is vacuum dried 12h and obtains white powder at 45 DEG C, is Azilsartan potassium through XRPD testing result display drying sample Crystal formation C.
Embodiment 15
At 60 DEG C, Azilsartan (1.0g) is joined in sec-butyl acetate (15mL), add acetone (20mL) the most molten Solve, form solution, be cooled to 50 DEG C, add acetone (2mL) solution of 2 ethyl hexanoic acid potassium (0.5g), by reactant mixture slowly It is cooled to 0 DEG C, continues insulated and stirred 5h, filter, be vacuum dried 12h at 45 DEG C and obtain white powder, show through XRPD testing result Drying sample is Azilsartan potassium crystal formation C.
Embodiment 16
At 60 DEG C, Azilsartan (1.0g) is dissolved in dichloroethanes (15mL), forms mixture, mixed toward formed Compound adds oxolane (15mL) dissolve afterwards, form solution, after solution is cooled to 50 DEG C, add 2 ethyl hexanoic acid potassium (0.5g) acetone (2mL) solution, forms mixture, mixture is slowly cooled to 0 DEG C, continues insulated and stirred 5h, filters and receives Collection crystal, is vacuum dried 12h and obtains white powder at 45 DEG C, be that Azilsartan potassium is brilliant through XRPD testing result display drying sample Type C.
Embodiment 17
At 60 DEG C, Azilsartan (1.0g) is joined in hexamethylene (20mL), form mixture, add in mixture Enter oxolane (30mL) and form solution, after solution is cooled to 50 DEG C, add the oxolane of 2 ethyl hexanoic acid potassium (0.5g) (2mL) solution, forms mixture, mixture is slowly cooled to 0 DEG C, continues insulated and stirred 5h, crystal is collected by filtration, at 45 DEG C Vacuum drying 12h obtains white powder, is Azilsartan potassium crystal formation C through XRPD testing result display drying sample.
Embodiment 18
At 60 DEG C, Azilsartan (1.0g) is joined 1, in 2-dichloroethanes (15mL), after adding acetone (15mL) Dissolve, form solution, be cooled to 50 DEG C, add acetone (2mL) solution of 2 ethyl hexanoic acid potassium (0.5g), be slowly cooled to 0 DEG C, Continue insulated and stirred 5h, filter, be vacuum dried 12h at 45 DEG C and obtain white powder, through XRPD testing result display drying sample be Azilsartan potassium crystal formation C.
Embodiment 19
At 60 DEG C, Azilsartan (1.0g) is joined in hexamethylene (20mL), add acetone (25mL) and dissolve afterwards, shape Become solution, be cooled to 50 DEG C, add acetone (2mL) solution of 2 ethyl hexanoic acid potassium (0.5g), be slowly cooled to 0 DEG C, continue to protect Temperature stirring 5h, filters, and is vacuum dried 12h and obtains white powder at 45 DEG C, is A Qisha through XRPD testing result display drying sample Smooth ester potassium crystal formation C.
Embodiment 20
At 60 DEG C, by molten for the mixing that Azilsartan (1.0g) joins Isosorbide-5-Nitrae-dioxane (15mL) and acetone (15mL) In agent, dissolve, form solution, be cooled to 50 DEG C, add acetone (2mL) solution of 2 ethyl hexanoic acid potassium (0.5g), slowly lower the temperature To 0 DEG C, continue insulated and stirred 5h, filter, be vacuum dried 12h at 45 DEG C and obtain white powder, show through XRPD testing result and be dried Sample is Azilsartan potassium crystal formation C
Embodiment 21
At 60 DEG C, Azilsartan (1.0g) is joined in acetonitrile (15mL), form mixture, add in mixture Glycol dimethyl ether (15mL) dissolves afterwards, forms solution, is cooled to 50 DEG C, adds the ethylene glycol bisthioglycolate of 2 ethyl hexanoic acid potassium (0.5g) Methyl ether (2mL) solution, is slowly cooled to 0 DEG C, continues insulated and stirred 5h, filters, and is vacuum dried 12h and obtains white powder at 45 DEG C, It is Azilsartan potassium crystal formation C through XRPD testing result display drying sample.
Embodiment 22
At 60 DEG C, Azilsartan (1.0g) is joined acetone (15mL) and the mixed solution of oxolane (10mL) In, form solution, be cooled to 50 DEG C, add acetone (2mL) solution of 2 ethyl hexanoic acid potassium (0.5g), be slowly cooled to 0 DEG C, continue Continuous insulated and stirred 5h, filters, and is vacuum dried 12h and obtains white powder at 45 DEG C, through XRPD testing result display drying sample be Ah Qi Shatan ester potassium crystal formation C.
Embodiment 23
At 60 DEG C, Azilsartan (1.0g) is joined in acetonitrile (10mL), form mixture, add in mixture Acetone (15mL), forms solution, is cooled to 50 DEG C, adds acetone (2mL) solution of 2 ethyl hexanoic acid potassium (0.5g), slowly lowers the temperature To 0 DEG C, continue insulated and stirred 5h, crystal is collected by filtration, be vacuum dried 12h at 45 DEG C and obtain white powder, through XRPD testing result Display drying sample is Azilsartan potassium crystal formation C.
Embodiment 24
Azilsartan potassium salt (1.0g) is joined in acetone (300mL), is heated to backflow, form solution, by solution Slowly it is cooled to 0 DEG C, continues insulated and stirred 5h, filter, be vacuum dried 12h at 45 DEG C and obtain white powder, through XRPD testing result Display drying sample is Azilsartan potassium crystal formation C.
Embodiment 25
At 60 DEG C, Azilsartan potassium salt (1.0g) is joined in acetonitrile (200mL), form solution, be slowly cooled to 0 DEG C, continue insulated and stirred 5h, filter, be vacuum dried 12h at 45 DEG C and obtain white powder, show drying sample through XRPD testing result For Azilsartan potassium crystal formation C.
Embodiment 26: the preparation of Azilsartan potassium salt crystal formation D
At 60 DEG C, Azilsartan (1.0g) is dissolved in Isosorbide-5-Nitrae-dioxane (20mL), forms solution, be cooled to 50 DEG C, add Isosorbide-5-Nitrae-dioxane (2mL) solution of 2 ethyl hexanoic acid potassium (0.5g), be slowly cooled to 0 DEG C, continue insulated and stirred 5h, filters, and is vacuum dried 12h and obtains white powder at 45 DEG C, is Azilsartan potassium through XRPD testing result display drying sample Crystal formation D.
Embodiment 27: the preparation of Azilsartan potassium salt crystal formation D
At 60 DEG C, Azilsartan (1.0g) is dissolved in glycol dimethyl ether (35mL), forms solution, be cooled to 50 DEG C, add glycol dimethyl ether (2mL) solution of 2 ethyl hexanoic acid potassium (0.5g), be slowly cooled to 0 DEG C, continue insulated and stirred 5h, filters, and is vacuum dried 12h and obtains white powder at 45 DEG C, is Azilsartan potassium through XRPD testing result display drying sample Crystal formation D, as shown in Figure 5.
Embodiment 28: the preparation of Azilsartan potassium salt crystal formation D
Azilsartan potassium salt (1.0g) is joined in acetone (60mL), form mixture, in mixture, add two First sulfoxide (3mL), forms solution, is slowly cooled to 0 DEG C, continues insulated and stirred 5h, filters, and is vacuum dried 12h and obtains white at 45 DEG C Color powder, is Azilsartan potassium crystal formation D through XRPD testing result display drying sample.
Embodiment 29: the preparation of Azilsartan potassium salt crystal formation E
At 60 DEG C, Azilsartan (1.0g) is dissolved in chloroform (85mL), forms solution, be cooled to 50 DEG C, add 2- Acetone (2mL) solution of thylhexoic acid potassium (0.5g), is slowly cooled to 0 DEG C, continues insulated and stirred 5h, filters, vacuum at 45 DEG C Dry 12h obtains white powder, is Azilsartan potassium crystal formation E through XRPD testing result display drying sample, as shown in Figure 7.
Embodiment 30: the preparation of Azilsartan potassium salt crystal formation F
At 60 DEG C, Azilsartan (1.0g) is dissolved in tert-butyl acetate (200mL), forms solution, be cooled to 50 DEG C, Add tert-butyl acetate (2mL) solution of 2 ethyl hexanoic acid potassium (0.5g), be slowly cooled to 0 DEG C, continue insulated and stirred 5h, mistake Filter, is vacuum dried 12h and obtains white powder at 45 DEG C, be Azilsartan potassium crystal formation F through XRPD testing result display drying sample, As shown in Figure 9.
Embodiment 31: the preparation of Azilsartan potassium salt crystal formation F
At 60 DEG C, Azilsartan potassium salt (1.0g) is joined in tert-butyl acetate (60mL), form mixture, toward mixed Compound adds N, N'-dimethylformamide (3mL), forms solution, be slowly cooled to 0 DEG C, add tap water (100mL), analysis Go out white solid, continue insulated and stirred 5h, filter, be vacuum dried 12h at 45 DEG C and obtain white powder, show through XRPD testing result Drying sample is Azilsartan potassium crystal formation F.
Embodiment 32: the preparation of Azilsartan potassium salt crystal formation G
At 60 DEG C, Azilsartan (1.0g) is dissolved in carbon tetrachloride (15mL), forms mixture, add oxolane (18mL) dissolve after, form solution, be cooled to 50 DEG C, add oxolane (2mL) solution of 2 ethyl hexanoic acid potassium (0.5g), slowly Slowly it is cooled to 0 DEG C, continues insulated and stirred 5h, filter, be vacuum dried 12h at 45 DEG C and obtain white powder, show through XRPD testing result Show that drying sample is Azilsartan potassium crystal formation G.
Embodiment 33: the preparation of Azilsartan potassium salt crystal formation H
Azilsartan (1.0g) is joined in toluene (15mL), form mixture, in mixture, add Isosorbide-5-Nitrae-two After oxygen six ring (30mL), form solution, be cooled to 50 DEG C, add the Isosorbide-5-Nitrae-dioxane (2mL) of 2 ethyl hexanoic acid potassium (0.5g) Solution, is slowly cooled to 0 DEG C, continues insulated and stirred 5h, filters, and is vacuum dried 12h and obtains white powder, detect through XRPD at 45 DEG C Result display drying sample is Azilsartan potassium crystal formation H.
Embodiment 34: the preparation of Azilsartan potassium salt crystal formation H
Azilsartan (1.0g) is joined in ethyl acetate (15mL), form mixture.1 is added in mixture, 4-dioxane (20mL) dissolves afterwards, forms solution, is cooled to 50 DEG C, adds the Isosorbide-5-Nitrae-dioxy six of 2 ethyl hexanoic acid potassium (0.5g) Ring (2mL) solution, is slowly cooled to 0 DEG C, continues insulated and stirred 5h, filters, and is vacuum dried 12h and obtains white powder, warp at 45 DEG C XRPD testing result display drying sample is Azilsartan potassium crystal formation H.
Embodiment 35: the preparation of Azilsartan potassium salt crystal formation H
Azilsartan (1.0g) is joined in the secondary ethyl ester of acetic acid (15mL), form mixture, add in mixture Isosorbide-5-Nitrae-dioxane (15mL) dissolves afterwards, forms solution, is cooled to 50 DEG C, adds the Isosorbide-5-Nitrae-dioxy of 2 ethyl hexanoic acid potassium (0.5g) Six rings (2mL) solution, is slowly cooled to 0 DEG C, continues insulated and stirred 5h, filters, and is vacuum dried 12h and obtains white powder at 45 DEG C, It is Azilsartan potassium crystal formation H through XRPD testing result display drying sample.
Embodiment 36: the preparation of Azilsartan potassium salt crystal formation H
Azilsartan potassium salt (1.0g) is joined in glycol dimethyl ether (40mL), form mixture, toward mixture Middle addition N, N'-dimethylformamide (10mL), dissolves, and forms solution, is slowly cooled to 20 DEG C, separates out a large amount of solid, continues Insulated and stirred 5h, filters, and is vacuum dried 12h and obtains white powder at 45 DEG C, is A Qi through XRPD testing result display drying sample Husky smooth ester potassium crystal formation H.
Embodiment 37: the preparation of Azilsartan potassium salt crystal formation I
At 60 DEG C, Azilsartan (1.0g) is dissolved in acetonitrile (90mL), forms solution, be cooled to 50 DEG C, add 2- Acetone (2mL) solution of thylhexoic acid potassium (0.5g), is slowly cooled to 0 DEG C, continues insulated and stirred 5h, filters, vacuum at 45 DEG C Dry 12h obtains white powder, is Azilsartan potassium crystal formation I through XRPD testing result display drying sample, as shown in figure 13.
Embodiment 38: the preparation of Azilsartan potassium salt crystal formation J
Azilsartan potassium (1.0g) is joined in acetone (40mL), form mixture, in mixture, add water (1mL) dissolve after, form solution, be cooled to 50 DEG C, continuously add water (100mL) and be slowly cooled to 0 DEG C, insulated and stirred 5h, mistake Filter, is vacuum dried 12h and obtains white powder at 45 DEG C, be Azilsartan potassium crystal formation J through XRPD testing result display drying sample.
Embodiment 39: the preparation of Azilsartan potassium salt crystal formation J
At 60 DEG C, Azilsartan (1.0g) is joined the mixed of glycol dimethyl ether (15mL) and oxolane (15mL) Close in solution, dissolve, form solution, be cooled to 50 DEG C, add oxolane (2mL) solution of 2 ethyl hexanoic acid potassium (0.5g), Slowly it is cooled to 0 DEG C, continues insulated and stirred 5h, filter, be vacuum dried 12h at 45 DEG C and obtain white powder, through XRPD testing result Display drying sample is Azilsartan potassium crystal formation J, as shown in figure 14.
Embodiment 40: the preparation of Azilsartan potassium salt crystal formation J
At 60 DEG C, Azilsartan potassium salt (1.0g) is joined in dichloromethane (60mL), form mixture, toward mixing Thing adds dimethyl sulfoxide (4mL), dissolves, form solution, be slowly cooled to 0 DEG C, continue insulated and stirred 5h, filter, at 45 DEG C Vacuum drying 12h obtains white powder, is Azilsartan potassium crystal formation J through XRPD testing result display drying sample.
Embodiment 41: the preparation of Azilsartan potassium salt crystal formation J
At 60 DEG C, Azilsartan potassium salt (1.0g) is joined in acetone (40mL), form mixture, in mixture Add glycol dimethyl ether (20mL) and water (4mL), dissolve, form solution, be slowly cooled to 0 DEG C, continue insulated and stirred 5h, mistake Filter, is vacuum dried 12h and obtains white powder at 45 DEG C, be Azilsartan potassium crystal formation J through XRPD testing result display drying sample.
Embodiment 42: the preparation of Azilsartan potassium salt crystal formation J
At 60 DEG C, Azilsartan potassium salt (1.0g) is joined in acetonitrile (40mL), form mixture, in mixture Add tap water (1mL), dissolve, form solution, be slowly cooled to 0 DEG C, continue to add tap water (60mL), separate out a large amount of solid Body, insulated and stirred 5h, filter, at 45 DEG C be vacuum dried 12h obtain white powder, through XRPD testing result display drying sample be Ah Qi Shatan ester potassium crystal formation J.
Embodiment 43: the preparation of Azilsartan potassium salt crystal formation J
At 60 DEG C, Azilsartan potassium salt (1.0g) is joined in acetonitrile (40mL), form mixture, in mixture Add N-Methyl pyrrolidone (20mL), dissolve, form solution, be slowly cooled to 0 DEG C, add tap water (120mL), continue to protect Temperature stirring 5h, filters, and is vacuum dried 12h and obtains white powder at 45 DEG C, is A Qisha through XRPD testing result display drying sample Smooth ester potassium crystal formation J.
Embodiment 44: the preparation of Azilsartan potassium salt crystal formation K
At 60 DEG C, Azilsartan potassium (1.0g) is joined in acetonitrile (100mL), dissolve, form solution, slowly lower the temperature To 0 DEG C, continue insulated and stirred 5h, filter, be vacuum dried 12h at 45 DEG C and obtain white powder, show through XRPD testing result and be dried Sample is Azilsartan potassium crystal formation K.
Embodiment 45: the preparation of Azilsartan potassium salt crystal formation L
Azilsartan potassium (1.0g) is joined in oxolane (20mL), form mixture, add in mixture Water (1mL) dissolves afterwards, forms solution, is down to 50 DEG C, continuously adds water (150mL) and be slowly cooled to 0 DEG C, insulated and stirred 5h, mistake Filter, is vacuum dried 12h and obtains white powder at 45 DEG C, be Azilsartan potassium crystal formation L through XRPD testing result display drying sample.
Embodiment 46: the preparation of Azilsartan potassium salt crystal formation L
At 60 DEG C, Azilsartan potassium salt (1.0g) is joined in oxolane (60mL), form mixture, toward mixing Thing adds N-Methyl pyrrolidone (3mL), dissolves, form solution, be slowly cooled to 0 DEG C, add tap water (100mL), analysis Go out white solid, continue insulated and stirred 5h, filter, be vacuum dried 12h at 45 DEG C and obtain white powder, show through XRPD testing result Drying sample is Azilsartan potassium crystal formation L.
Embodiment 47: the preparation of Azilsartan potassium salt crystal formation L
Azilsartan potassium salt (1.0g) is joined in dioxane (50mL), form mixture, in mixture again Add N-N'-dimethylformamide (10mL), dissolve, form solution, be slowly cooled to 0 DEG C, add tap water (50mL), continue Insulated and stirred 5h, filters, and is vacuum dried 12h and obtains white powder at 45 DEG C, is A Qi through XRPD testing result display drying sample Husky smooth ester potassium crystal formation L.
Embodiment 48: the preparation of Azilsartan potassium salt crystal formation L
Azilsartan potassium salt (1.0g) is joined in oxolane (40mL), form mixture, in mixture again Add glycol dimethyl ether (20mL) and tap water (1mL), dissolve, form solution, be slowly cooled to 0 DEG C, continuously add from the beginning Water (100mL), insulated and stirred 5h, filters, is vacuum dried 12h and obtains white powder at 45 DEG C, show through XRPD testing result and be dried Sample is Azilsartan potassium crystal formation L.
Embodiment 49
Stability experiment
The stability experiment of Azilsartan potassium crystal formation C is carried out under the conditions of following two:
Storage condition 1: place 3 months and 6 months under sealing state under the conditions of 40 DEG C of ./RH75% as a result, after 6 months Do not find that crystal formation C is transformed into other crystal formations.During testing, compared with the content of total impurities when just starting to place, total after placement Miscellaneous content is not changed in.
Storage condition 2: under non-tight state, after placing 3 months under the conditions of 40 DEG C of ./RH75%, crystal formation C does not changes Become other crystal formations, but total impurities content increases.
Embodiment 50
Solubility experiment
Under room temperature, the Azilsartan potassium each 0.50g of crystal formation C, D, F, H, J and L is added in solvent, every 5 minutes strengths Shake 30 seconds, make solid dissolve, then observe dissolving situation, as during without visual visible particles of solute, be i.e. considered as dissolving.
The dissolubility data of Azilsartan potassium crystal formation C, D, F, H, J and L is as follows:
Methanol Ethanol Acetone THF Ethyl acetate Result
Crystal formation C 5ml 6ml 8ml 13ml 10ml Dissolve
Crystal formation D 4ml 5ml 9ml 16.5ml 12ml Dissolve
Crystal formation F 4.5ml 6ml 12ml 15ml 16ml Dissolve
Crystal formation H 6ml 8ml 10ml 14ml 13ml Dissolve
Crystal formation J 4ml 5.5ml 8ml 12ml 11ml Dissolve
Crystal formation L 5ml 6ml 11ml 17ml 14ml Dissolve
Embodiment 51
A kind of tablet containing Azilsartan potassium salt crystal formation A, comprising: Azilsartan potassium salt crystal formation A, mannitol, rich Horse acid, sodium hydroxide, hydroxypropyl cellulose, cross-linked cellulose sodium, microcrystalline Cellulose, magnesium stearate.
Embodiment 52
A kind of tablet containing Azilsartan potassium salt crystal formation B, comprising: Azilsartan potassium salt crystal formation B, mannitol, rich Horse acid, sodium hydroxide, hydroxypropyl cellulose, cross-linked cellulose sodium, microcrystalline Cellulose, magnesium stearate.
Embodiment 53
A kind of tablet containing Azilsartan potassium salt crystal formation C, comprising: Azilsartan potassium salt crystal formation C, mannitol, rich Horse acid, sodium hydroxide, hydroxypropyl cellulose, cross-linked cellulose sodium, microcrystalline Cellulose, magnesium stearate.
Embodiment 54
A kind of tablet containing Azilsartan potassium salt crystal formation D, comprising: Azilsartan potassium salt crystal formation D, mannitol, rich Horse acid, sodium hydroxide, hydroxypropyl cellulose, cross-linked cellulose sodium, microcrystalline Cellulose, magnesium stearate.
Embodiment 55
A kind of tablet containing Azilsartan potassium salt crystal formation H, comprising: Azilsartan potassium salt crystal formation H, mannitol, rich Horse acid, sodium hydroxide, hydroxypropyl cellulose, cross-linked cellulose sodium, microcrystalline Cellulose, magnesium stearate.
Embodiment 56
A kind of tablet containing Azilsartan potassium salt crystal formation L, comprising: Azilsartan potassium salt crystal formation L, mannitol, rich Horse acid, sodium hydroxide, hydroxypropyl cellulose, cross-linked cellulose sodium, microcrystalline Cellulose, magnesium stearate.

Claims (11)

1. a crystal formation for Azilsartan potassium salt, described crystal formation is crystal formation C, in its X-ray powder diagram at 2 θ is There is peak 6.20,12.64,13.36,14.48,16.00,18.70,20.30,21.38,22.78,23.80,25.04 positions.
Crystal formation C the most according to claim 1, is 6.20 at 2 θ in its X-ray powder diagram, 12.64,13.36, 14.02,14.48,16.00,17.74,18.12,18.70,20.30,21.38,22.78,23.80,25.04,25.6,27.52, 28.16,28.32,31.32 there is peak position.
Crystal formation C the most according to claim 1, its X-ray powder diagram is as shown in Figure 3.
4. the method preparing Azilsartan potassium salt crystal formation as described in claim 1-3 is arbitrary, described preparation method bag Include and dissolve Azilsartan in a solvent, form solution, in solution, add potassium salt soln, form crystalline substance at a proper temperature Body, wherein, described solvent is molten selected from dimethylformamide, dimethyl sulfoxide, N-Methyl pyrrolidone, water, ether solvents, ketone Agent, esters solvent, aromatic hydrocarbon solvent, alkane solvents, nitrile solvents or a combination thereof.
Method the most according to claim 4, described potassium salt is organic acid potassium salt or inorganic acid salt, including potassium nitrate, sulphuric acid Potassium, potassium sulfite, Potassium bromate., potassium bicarbonate, potassium thiocyanate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, Potassium Hydrogen Phthalate, second Acid potassium, potassium formate, di(2-ethylhexyl)phosphate tert-butyl ester potassium, glycyrrhizic acid dipotassium, 2 ethyl hexanoic acid potassium, ehtyl potassium xanthate, potassium sorbate or A combination thereof.
6. preparing a method for Azilsartan potassium salt crystal formation as described in claim 1-3 is arbitrary, described preparation method includes Being dissolved in a solvent by Azilsartan potassium salt, then crystallize from solvent, wherein, described solvent is selected from dimethyl formyl Amine, dimethyl sulfoxide, N-Methyl pyrrolidone, water, ether solvents, ketones solvent, esters solvent, aromatic hydrocarbon solvent, alkanes are molten Agent, nitrile solvents or a combination thereof.
7., according to the arbitrary described method of claim 4-6, described ether solvents is selected from methyltetrahydrofuran, oxolane, dioxy Six rings, glycol dimethyl ether or methyl tertiary butyl ether(MTBE)；Described ketones solvent is selected from acetone, butanone or 4-methyl-2 pentanone；Institute State esters solvent selected from ethyl acetate, isopropyl acetate, n-butyl acetate, sec-butyl acetate or tert-butyl acetate；Described alkane Kind solvent selected from dichloromethane, 1,2-dichloroethanes, chloroform, carbon tetrachloride, nitroethane, normal hexane, hexamethylene or pentane or Normal heptane；Described aromatic hydrocarbon solvent is selected from benzene, toluene or dimethylbenzene；Described nitrile solvents is selected from acetonitrile or Cyanoacetyl-Cyacetazid.
Preparation method the most according to claim 7, when solvent selected from acetone, 4-methyl-2 pentanone, ethyl acetate, two Chloromethanes, isobutyl acetate, sec-butyl acetate, methyltetrahydrofuran, nitroethane, 1,2-dichloroethanes, dioxane, second two When one in diethylene glycol dimethyl ether, acetonitrile, oxolane, hexamethylene or a combination thereof, obtain Azilsartan potassium crystal formation C.
9. a pharmaceutical composition, comprises crystal formation C and the one of Azilsartan potassium salt as described in any one of claim 1-3 Or multiple inert excipient or carrier.
Compositions the most according to claim 9, described inert excipient or carrier are mannitol, fumaric acid, hydroxide Sodium, hydroxypropyl cellulose, cross-linked cellulose sodium, microcrystalline Cellulose, magnesium stearate or a combination thereof.
Medicine as described in the crystal formation C of the 11. Azilsartan potassium salt as described in any one of claim 1-3 or claim 9 or 10 Compositions application in the medicine of preparation prevention or treatment hypertension.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100503605C (en) * 2004-02-25 2009-06-24 武田药品工业株式会社 Benzimidazole derivative and its use as AII receptor antagonist
WO2010075347A2 (en) * 2008-12-23 2010-07-01 Takeda Pharmaceutical Company Limited Methods of treating hypertension with at least one angiotensin ii receptor blocker and chlorthalidone
CN102225203A (en) * 2011-06-29 2011-10-26 北京阜康仁生物制药科技有限公司 Pharmaceutical composition used for lowering blood pressure

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012090043A1 (en) * 2010-12-29 2012-07-05 Jubilant Life Sciences Limited Novel solid state forms of azilsartan medoxomil and preparation thereof
CN102351853B (en) 2011-08-29 2014-03-12 石药集团欧意药业有限公司 Azilsartan medoxomil compound, preparation method and medicinal composition thereof
WO2013088384A2 (en) 2011-12-15 2013-06-20 Jubilant Life Sciences Limited Solid state forms of azilsartan and azilsartan medoxomil monopotassium and preparation thereof
WO2013124748A1 (en) 2012-02-20 2013-08-29 Alembic Pharmaceuticals Limited Novel polymorphs of azilsartan medoxomil potassium
WO2014020381A1 (en) * 2012-08-01 2014-02-06 Alembic Pharmaceuticals Limited Novel crystalline form of azilsartan medoxomil potassium

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100503605C (en) * 2004-02-25 2009-06-24 武田药品工业株式会社 Benzimidazole derivative and its use as AII receptor antagonist
WO2010075347A2 (en) * 2008-12-23 2010-07-01 Takeda Pharmaceutical Company Limited Methods of treating hypertension with at least one angiotensin ii receptor blocker and chlorthalidone
CN102225203A (en) * 2011-06-29 2011-10-26 北京阜康仁生物制药科技有限公司 Pharmaceutical composition used for lowering blood pressure

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
抗高血压新药选择性AT1亚型血管紧张素II受体拮抗剂——阿齐沙坦酯;张亚安等;《药学与临床研究》;20110630;第19卷(第3期);262-264 *

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